1. Field of the Invention
The present invention relates to a dipeptidyl peptidase-IV inhibitor and the like.
2. Description of the Related Art
Dipeptidyl peptidase-IV (hereinafter referred to also as “DPP-4”) is a multifunctional transmembrane glycoprotein having an N-terminal dipeptidase activity. It is present on the cells of most mammalian animals, and its presence in various tissues such as liver, kidney, small intestine, salivary gland, blood cells, plasma, and the like raises an assumption that it plays a broad range of in vivo roles, which makes it an enzyme which is attractive as a drug discovery target in these days.
The dipeptidyl peptidase-IV is known as a lytic enzyme to incretin's glucagon-like peptide-1 (hereinafter referred to as “GLP-1”) and glucose-dependent insulinotropic polypeptide (hereinafter referred to as “GIP”). This GLP-1 is released after meal, and has a diverse effect including insulin biosynthesis- and secretion-responsive glucose inducible stimulation, glucagon secretion suppression, gene expression regulation, B-cell trophic effect, food intake suppression, and gastric content output slowing. In addition, dipeptidyl peptidase-IV inhibition serves to suppress degradation of incretin's GLP-1 and GIP, whose concentrations in blood are then elevated. As a result, the insulin secretion is promoted and the blood sugar level is reduced, as is known. This incretin-driven insulin secretion promotion requires a hyperglycemic level as an operating condition. Accordingly, the dipeptidyl peptidase-IV inhibition in a diabetes case caused by a reduction in insulin secretion among type II diabetes is at a lower risk of a side effect such as hypoglycemia which is caused by conventional insulin secretion promotors.
As discussed above, the dipeptidyl peptidase-IV inhibitor having a dipeptidyl peptidase-IV activity inhibiting effect is to be utilized as an anti-diabetic agent. Nevertheless, the dipeptidyl peptidase-IV inhibitor is regarded still as a new type therapeutic agent when compared with the insulin secretion suppressing agents and the glucose absorption inhibiting agents. In addition, the first step of the diabetic therapy involves dietetic treatment and kinesitherapy, whose inability, in some cases, of controlling the blood sugar level leads, to use of pharmaceuticals for treating diabetes. As a result, it can be considered that a substance having a dipeptidyl peptidase-IV inhibiting activity can be provided as a supplement or a food additive contributes greatly to the improvement of the blood sugar level.
Patent Document 1 discloses that a dicyclic pyrimidine can be used as a dipeptidyl peptidase-IV inhibitor for the therapy or the prophylaxis of diabetes.
Patent Document 2 discloses that a casein was subjected to an alkaline degradation while controlling pH and temperature followed by an enzymatic hydrolysis using a preparation of various enzymes such as a protease to obtain a hydrolysate which was then separated and purified into various peptides, from which one having a dipeptidyl peptidase-IV inhibiting effect was further identified. Otherwise, there are disclosures relating to food-derived dipeptidyl peptidase-IV inhibiting substances (for example, see Patent Documents 3 to 5).
Table 2 of Patent Document 6 indicates isolated peptides each of which was separated as a single peptide from a casein or whey hydrolysate, namely, IPI, LPL, KVLP, LPVPQK, VPLGTQ, VPYPQ, PLLQ, GPFP, LPVPQ, LPQYL, MPLW, YVPEPF, PQSVLS, PFP, LPVP, EMPFPK, LPLP, GPFPIIV, APFPE, HPIK, and APFPEVF, and the results of the dipeptidyl peptidase-IV inhibiting tests of these isolated peptides were disclosed.